The Akt/mTOR and MNK/eIF4E pathways rewire the prostate cancer translatome to secrete HGF, SPP1 and BGN and recruit suppressive myeloid cells.

Autor: Brina D; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Ponzoni A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Ima Biotech, Lille, France., Troiani M; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland., Calì B; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Pasquini E; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Attanasio G; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Mosole S; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Mirenda M; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Evotec, Toulouse, France., D'Ambrosio M; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Imperial College London, London, UK., Colucci M; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Guccini I; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Institute of Molecular Health Sciences, ETH Zurich, Zurich, Switzerland., Revandkar A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Harvard Medical School, Massachusetts General Hospital Cancer Center, Boston, MA, USA., Alajati A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Department of Urology, Universitätklinikum Bonn, Bonn, Germany., Tebaldi T; Yale Cancer Center and Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA., Donzel D; Institute of Biophysics, CNR Unit at Trento, Povo, Italy., Lauria F; Institute of Biophysics, CNR Unit at Trento, Povo, Italy., Parhizgari N; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.; Biosun Pharmed, Kordan, Iran., Valdata A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Maddalena M; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Calcinotto A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Bolis M; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland.; Bioinformatics Core Unit, Swiss Institute of Bioinformatics, Bellinzona, Switzerland.; Computational Oncology Unit, Department of Oncology, Istituto di Richerche Farmacologiche 'Mario Negri' IRCCS, Milano, Italy., Rinaldi A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland., Barry S; IMED Oncology AstraZeneca, Li Ka Shing Centre, Cambridge, UK., Rüschoff JH; Department of Pathology and Molecular Pathology, University Hospital Zurich (USZ), Zurich, Switzerland., Sabbadin M; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy., Sumanasuriya S; Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK., Crespo M; Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK., Sharp A; Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK., Yuan W; Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK., Grinu M; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA., Boyle A; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA., Miller C; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA., Trotman L; Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, USA., Delaleu N; 2cSysBioMed, TI, Contra, Switzerland., Fassan M; Veneto Institute of Oncology, IOV-IRCCS, Padua, Italy.; Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy., Moch H; Department of Pathology and Molecular Pathology, University Hospital Zurich (USZ), Zurich, Switzerland., Viero G; Institute of Biophysics, CNR Unit at Trento, Povo, Italy., de Bono J; Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.; The Royal Marsden Hospital, London, UK., Alimonti A; Institute of Oncology Research, Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. andrea.alimonti@ior.usi.ch.; Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland. andrea.alimonti@ior.usi.ch.; Department of Medicine, Venetian Institute of Molecular Medicine, University of Padova, Padova, Italy. andrea.alimonti@ior.usi.ch.; Department of Health Sciences and Technology, Eidgenössische Technische Hochschule (ETH) Zürich, Zurich, Switzerland. andrea.alimonti@ior.usi.ch.
Jazyk: angličtina
Zdroj: Nature cancer [Nat Cancer] 2023 Aug; Vol. 4 (8), pp. 1102-1121. Date of Electronic Publication: 2023 Jul 17.
DOI: 10.1038/s43018-023-00594-z
Abstrakt: Cancer is highly infiltrated by myeloid-derived suppressor cells (MDSCs). Currently available immunotherapies do not completely eradicate MDSCs. Through a genome-wide analysis of the translatome of prostate cancers driven by different genetic alterations, we demonstrate that prostate cancer rewires its secretome at the translational level to recruit MDSCs. Among different secreted proteins released by prostate tumor cells, we identified Hgf, Spp1 and Bgn as the key factors that regulate MDSC migration. Mechanistically, we found that the coordinated loss of Pdcd4 and activation of the MNK/eIF4E pathways regulate the mRNAs translation of Hgf, Spp1 and Bgn. MDSC infiltration and tumor growth were dampened in prostate cancer treated with the MNK1/2 inhibitor eFT508 and/or the AKT inhibitor ipatasertib, either alone or in combination with a clinically available MDSC-targeting immunotherapy. This work provides a therapeutic strategy that combines translation inhibition with available immunotherapies to restore immune surveillance in prostate cancer.
(© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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